Project Summary We are developing a novel tool for disease diagnosis called the indicator cell assay platform (iCAP) that uses standardized cultured cells as biosensors to detect disease status of patients from blood or cerebral spinal fluid (CSF) samples. Here, we propose to establish proof of concept for applying the assay to drug discovery by initiating development of the iCAP for drug selection for Alzheimer?s disease (AD) as described below. The iCAP we are developing for diagnosis of AD uses standardized normal human neurons as biosensors. In the assay, neurons are exposed to plasma (or CSF) samples from normal and AD patients, and then the global differential transcriptional responses of the neurons are used to define disease and normal signatures. The assay is then used to diagnose new patients based on their iCAP signatures. Cellular responses in the iCAP reflect known AD pathology; we have identified significant overlap in genes of the AD iCAP signature with AD-specific transcriptional signatures identified in patient brain sections at autopsy. Therefore, the iCAP is not only a diagnostic tool, but also a unique cellular model of AD reflecting the response of initially healthy neurons to disease signals in the patient samples. Here we propose to use the iCAP as a cellular model of AD to select and evaluate FDA-approved drugs as candidates for treating early-stage AD. We will use an approach called inverse gene expression profiling, which predicts drug treatments for diseases by identifying drugs that elicit cellular gene expression profiles that are inverse to profiles of the disease state. Our approach has 2 specific aims: 1) We will computationally screen a library of gene expression profile responses to various drugs to identify those that are the inverse of existing iCAP signatures for early-stage AD, and 2) We will experimentally test the drugs by exposing them to neurons in the iCAP, and identifying those that can correct the iCAP early-stage AD signature and (partially) restore the normal signature. Our goals are to establish feasibility of using the iCAP for drug discovery, and to identify new drug candidates for early-stage AD that will be further characterized in an animal model in a Phase II study. Our long term goals are to establish the iCAP as a robust tool for drug selection that can be integrated into drug- testing pipelines, and to identify new drugs to prevent, cure or slow the progression of AD. As the assay generates personal signatures for individual patients, we anticipate that the fully developed iCAP will have capability to rapidly assess patient-specific drug effects for precision medicine (without the need for generating patient-derived neurons). PreCyte Confidential